The central aim of the study, in response to RFA-04-MH-102, is to differentiate the alterations in cognitive and affective circuitry in pediatric bipolar disorder (PBD) and attention deficit hyperactivity disorder (ADHD) relative to typically developing operations. Our research is specifically novel to move the field forward by probing the interface of the affective and cognitive circuits to delineate differences in the neural signatures of these disorders to further refine and validate them. PBD and ADHD are the two prototypic disorders that allow a meticulous research inquiry into the symptom-based circuits. Our mechanistic understanding of these circuits especially enhances our understanding of the dimensional functions of affect and cognition, and guide rational pharmacological treatment for ADHD and PBD. This study has an extremely high public health impact given the high rates of suicidal behavior, academic failure, poor recovery and high rates of relapse in this population. Many children are diagnosed after a 10 year period in which they are misdiagnosed as ADHD and/or given inappropriate medications such as stimulants. Similarly, ADHD is associated with academic underachievement and low self esteem, often leading to incorrect diagnosis and treatment. Beyond this challenge, the foremost priorities in this field are the pursuit of developmentally sensitive methods, translation of concepts from animal models to event-related paradigms so as to probe cognitive and affective circuitry in pediatric preclinical and clinical population, and employing innovative neurocognitive studies and functional (fMRI) and high resolution diffusion tensor (DTI) imaging methods to take the scientific approaches to a new era of inquiry. Our proposal adopts these challenges in our specific aims, building on our experience with these methods in our preliminary studies. Our first specific aim is to map the functional operations at the interface of affective and cognitive circuitry in PBD and ADHD-combined type relative to healthy controls (HC). Using an affective color matching task that engages attentional circuitry under emotional challenge, we predict that the subcortical regions are differentially engaged in PBD and ADHD with increased amygdala activity in PBD, relative to HC and ADHD;and more prominent abnormalities in caudate in the ADHD relative to HC and PBD. Higher cortical centers such as ventrolateral prefrontal cortex (VLPFC) and dorsolateral prefrontal cortex (DLPFC) may both be affected in PBD and ADHD groups relative to HC. However, the ADHD group may show decreased DLPFC activation relative to PBD, and the PBD group may show decreased VLPFC activation in relation to ADHD. The cognitive and affective portions of the anterior cingulate cortex may also be differentially engaged in PBD relative to ADHD. We will also use the corresponding battery of neurocognitive tasks to obtain behavioral data on attentional tasks performed under emotional challenge. Our second specific aim is to characterize, using high resolution DTI, the integrity of white matter tracts that support the interface between cognitive and affective function in PBD and ADHD-combined type. To accomplish this aim, DTI data are obtained from the color coded tracts that will allow us to measure fractional anisotropy (FA), apparent diffusion co-efficient (ADC) and fiber coherence index in the tracts that connect the fronto-striatal regions and the fronto-limbic regions. Consistent with our preliminary results, we predict that patients with ADHD and PBD will show lower global FA than HC in anterior corona radiata (ACR), anterior limb of the internal capsule (ALIC). Patients with PBD will have lower FA than ADHD in the uncinate fasiculus that stretches between frontal and limbic regions. Patients with ADHD will have lower FA than PBD in the cingulum and inferior frontal longitudinal fasciculus, the white matter tracts between prefrontal regions and the caudate. Our instrumental goal is to probe the function and structure of fronto-limbic and fronto-striatal circuits that will offer a working model of brain operations in PBD and ADHD by merging the fMRI and DTI findings. This "proof of concept" cross sectional study consists of unmedicated youth with PBD (with and without comorbid ADHD;n=40) who are manic or hypomanic, ADHD-combined type (n=25), and healthy controls (HC;n=25) in the developmentally sensitive age group of 13 to 16 year olds, and is designed to be completed within a two-year time frame. All subjects are clinically characterized using Washington University Schedule for Schizophrenia and Affective Disorders, a semi structured diagnostic interview, in addition to clinical interview, Young Mania Rating Scale, Child Depression Rating Scale-Revised, ADHD Rating Scale Revised, and Conners'Parent Rating Scale-Revised to identify the clinical phenotypes of PBD and ADHD. We are uniquely positioned in conducting the study with the strong collaboration between the PI who directs the pediatric bipolar research and clinical programs and Dr. Mark Stein who directs the ADHD program at UIC. Our established collaborators include Drs Sweeney, Zhou, and Little, who are pioneers in the fields of highly advanced fMRI and DTI technology. Finally, this study is aligned with the mission of the American Recovery and Reinvestment Act of 2009 (Recovery Act) to create new employment opportunities for research staff. Further, given the furious debate on misdiagnosing and mistreating children in the media, timing is also excellent to rightfully claim back the problem to be solved on a scientific basis such as that proposed here. PUBLIC HEALTH RELEVANCE: Pediatric bipolar disorder (PBD) and attention deficit hyperactivity disorder (ADHD) are often poorly differentiated, misdiagnosed and mistreated, given their overlapping clinical symptoms. Therefore, the proposed study aims to delineate the functioning of the underlying and interfacing affective and cognitive neural circuitry between unmedicated patients with PBD and ADHD using novel neurocognitive studies, and functional and diffusion tensor imaging technology. Mechanistic comprehension of the neural circuitry function will enhance our understanding of the dimensional functions of affect and cognition, and guide rational pharmacological treatment for ADHD and PBD.